ClinVar Miner

Submissions for variant NM_000090.4(COL3A1):c.2229+1G>A

dbSNP: rs1576468385
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000793968 SCV000933349 likely pathogenic Ehlers-Danlos syndrome, type 4 2018-09-16 criteria provided, single submitter clinical testing In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in COL3A1 are known to be pathogenic (PMID: 24922459). This variant has not been reported in the literature in individuals with COL3A1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 31 of the COL3A1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.
Ambry Genetics RCV002424801 SCV002728879 likely pathogenic Familial thoracic aortic aneurysm and aortic dissection 2023-11-03 criteria provided, single submitter clinical testing The c.2229+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 31 of the COL3A1 gene. This variant was reported in an individual with concerns for COL3A1-related Ehlers-Danlos syndrome (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.

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